- disubstituted -



United States Patent- "c 3,083,149

Patented Mar. 26, 1963 1 2 3 083 140 no undesirable side effects. For instance, it does not N {p (3,3 EESUBSTETUTED 1 AZETEHNYL possess anticholinesterasic activity, shown by many com- RTE-SKY} BENZOYL] 3,4,5 TRHMETHOXY- p s of similar structur BENZAMEBE AND PHARMACEUTICAL COM- The process for preparing compounds having the gen- POSEYEUNS 5 eral Formula I comprises reacting p-hydroxy-benzylamine Emma T9553; 5 Simflnes 7323550, Tim), Switzerland with trimethoxybenzoic acid chloride in an inert organic assignor to Lepetit S.p.A., Milan, Italy No Drawing. Filed Mar. 8, 1961, Ser. No. 4,153 Saints priority, appiieation Great Britain Mar. 13, 1960 solvent in the presence of a tertiary amine which may be aliphatic or heterocyclic, filtering the precipitated N-(phydroxybenzyl)-3 45-trimethoxybenzamide and heating C; as. 3. 167- 53 8 am C 10 at 65-70" an alkali metal salt of said N-(p-hydroxy- The present invention is concerned with pharmacologbenzyl)-3,4,5-trimethoxybenzamide with an N-chloroethically active compounds and a process for their preparayl-3,3-dialkylazetidine in an inert organic solvent, evaption. More particularly this invention relates to N-[pcrating the mixture to dryness, taking up the residue with (3,3 disubstituted 1 azetidinylethoxy) benzyl] 3, an organic solvent, filtering ofi the inorganic salt, evapo- 4,5-trimethoxybenzamide of the formula rating the solvent, taking up the residue with diethyl ether OCHQ /CE2 /R H O o--o ONHCHzOOH -CH2N\ /o I CH1 \R' OCHa (I) wherein R and R are the same or different and represent and precipitating the product from the diethyl ether solulower alkyl radicals. tion by the addition of light petroleum. The compounds of the invention are useful as anti- The reaction scheme is as follows:

(|)OHa no-Gonmm moo-@0001 0 CH3 I 1 CH2 /R HO-Q-Olig-NH-CO-QOOH; o1-oH2-oH2 N o (g Cz \R' OCH! /C2 /R HaCO- CO-NHOHz--OGHCHz-N o A) v cg \R' CH3 histaminic and antiemetic agents. For instance, the com- The N-chloroethyl-3,3-dialkylazetidine is prepared by pound of the above formula in which R and R are both adding a cold solution of 3,3-dialkylazetidine dropwise methyl shows a low degree of toxicity the LD being to a cold solution of ethylene oxide while keeping the in mice about 900 mg./kg./per oz.', 600 mg./kg. intramixture at about 0 under stirring, allowing the mixture peritoneally and 110 m g/kg. intravenously. In dogs, to stand at room temperature for a few days, and distillthis compound, when administered subcutaneously in ing the residue obtained after evaporation of the organic doses of 25-30 mg./kg., affords complete protection solvent in vacuo.

against vomiting caused by a subcutaneous injection of A chloroform solution of 3,3-dialkyl-l-(li-hydroxyapomorphine hydrochloride 0.1 mg./kg. A good protecethy1)-azetidine is then treated with thionyl chloride at a tion is also obtained with 20 mg./kg. By oral route, temperature below 10, the reaction mixture is heated at complete protection is afforded by about 5'0' mg./kg., boiling point, then cooled, poured into ice, and the aqueand a good degree of protection by 40 mg./l g. In comous layer made alkaline with a solution of Na CO and parison with known antiemetic substances, the comextracted with diethyl ether. The residue obtained after pound of the invention shows the advantage of causing evaporation of the solvent is then distilled in vacuo.

The following example is illustrative of the invention.

EXAMPLE l-(fi-Hydroxyethyl)-3,3-Dimerhylazetidine 4 forms which is collected. Yield 28 g. (54%), Ml. 95-97.

Iclaim:

1. An N [p (disubstituted-l-azetidinylethoxy)-ben- To a solution of 48 g. of ethylene oxide in 250 ml. of 5 zyl]-3,4,S-trimethoxybenzamide of the formula anhydrous ethanol, a solution of 85 g. of 3,3-dirnethylazetidine in 50 ml. of anhydrous ethanol is slowly added with stirring at about 0. After two days at room temperature the solvent is removed and the residue distilled. Yield 80 g. (62%), B.P. 80-83/24 mm.

1-(,B-Chloroethyl)-3,3-Dimethylazetidine To a solution of 25.8 g. of 1-(5-hydroxyethyl)-3,3-

dimethylazetidine in 80 ml. chloroform, 38 g. of thionyl chloride are added at a temperature below The reaction mixture is heated at boiling point. After cooling the mixture is poured into ice, the aqueous layer washed with chloroform, made alkaline with a solution of Na CO and extracted with diethyl ether. The residue obtained after evaporation of the solvent is then distilled in vacuo. Yield 20.3 g. (68%), B.P. 47-51/24 mm.

N- (p-Hydroxybenzyl)-3,4,5-Trimerhoxybenzamide To a solution of 21 g. of p-hydroxybenzylamine in anhydrous pyridine, a solution of 39 g. of trimethoxybenzoic acid chloride in anhydrous benzene is added dropwise over a period of minutes without exceeding 10. The mixture is then stirred for 6 hours at room temperature. A yellow precipitate is obtained and separated by filtration. Yield 35 g. (65%), M.P. 227-229.

N [p-(3,3-Dimethyl-1 -Azeridinyfethoxy) -Benzyl 3,4,5-Trimethoxybenzamide A solution of 31.7 g. of N-(p-hydroxybenzyl)-3,4,5- trimethoxybenzamide in 250 m1. of isopropyl alcohol is added dropwise to a solution of 2.3 g. of sodium in 250 ml. of isopropyl alcohol at -6570. The mixture is stirred for about minutes, then 16 g. N-chloroethyl-Er, 3-dirnethylazetidine are added dropwise and the mixture is stirred at the same temperature for 5 hours. The organic solvent and the excess of the free base are evaporated in vacuo, the residue is taken up with acetone and NaCl filtered off. The solvent is then evaporated and the residue taken up with diethyl ether, the undissolved portion is filtered oil and the solution concentrated to about 15 ml. By the addition of petroleum ether a precipitate OCH;; CH

OOH

CH2 R wherein R and R are lower alkyl, and a suitable pharmaceutical carrier.

4. A pharmaceutical composition in dosage unit form comprising from 0.01 to 1 gram of the compound of claim 1 together with a solid carrier.

5. A pharmaceutical composition in dosage unit form comprising from 0.01 to 1 gram of the compound of claim 1 together with a liquid diluent.

6. A pharmaceutical composition in dosage unit form comprising from 0.01 to 1 gram of an N-[p-(3,3-dimethyl 1 azetidinyl) benzyl] 3,4,5 trimethoxybenzamide together with a suitable diluent.

7. A pharmaceutical composition in dosage unit form comprising from 0.01 to 1 gram of an N-[p-(3,3-dimethyl- 1-azetidinyl)-benzyl]-3 ,4,5-trimethoxybenzamide together with a solid pharmaceutical carrier.

8. A pharmaceutical composition in dosage unit form comprising from 0.01 to 1 gram of an N-[p-(3,3-dimethyl 1 azetidinyl) benzyl] 3,4,5 trimethoxybenzarnide together with a liquid diluent.

References Cited in the file of this patent UNITED STATES PATENTS 2,870,145 Perron Jan. 20, 1959 2,870,146 Perron Jan. 20, 1959 2,879,293 Goldberg et al Mar. 24, 1959 OTHER REFERENCES Richter: Organic Chemistry, volume 4, page 5 (1947). Testa et 211.: Annalen, volume 635, pages 119-27 (1960). 

1. AN N - (P - (DISUBSTITUTED-1-AZETIDINYLETHOXY)-BENZYL)-3,4,5-TRIMETHOXYBENZAMIDE OF THE FORMULA
 3. A PHARMACEUTICAL COMPOSITION IN DOSAGE UNIT FORM, COMPRISING FROM 0.01 TO 1 GRAM OF AN N-(P-(3,3-DISUBSTITUTED - 1 - AZETIDINYLETHOXY0 - BENZYL) - 3,4,5 - TRIMETHOXYBENZAMIDE OF THE FORMULA 